Coronary artery spasm is widely accepted as the cause of myocardial ischemia in patients with variant angina. It may also play a role in an undetermined portion of the larger population of patients with ischemic heart disease. Despite the importance of this abnormal vascular reactivity, its mechanism remains obscure; the angiographic localization of spasm to areas of atherosclerotic involvement, however, provides a suggestion that physical and functional alterations of the coronary vessel may be causally related. Preliminary data from several laboratories support this hypothesis, but the duration of exposure to high cholesterol concentrations in the animals studied has been brief, and their relevance to the human disease condition is uncertain. In addition, the recent demonstration of the importance of the endothelium to vascular smooth muscle function is a critical new factor to be considered in the design of studies of the effect of atherosclerosis. We propose to investigate the effect of progressive atherosclerosis on coronary vascular reactivity in miniature swine. In vivo studies in conscious animals with coronary angiography, thermodilution coronary sinus flow and hemodynamic measurements will define epicardial coronary arterial and arteriolar reactivity to adrenergic, serotonin and histamine receptors. Arteriography will also allow visualization of the progression of atherosclerosis, which will be produced by an atherogenic diet alone in one experimental group, and by diet combined with balloon de-endothelialization in the other. After sacrifice of the animals at varying times throughout the year, tissue bath studies will allow the in vitro evaluation of reactivity in ring segments of epicardial arteries, localized as to their in vivo reactivity by arteriography. The degree of atherosclerotic involvement and the extent of endothelial damage will be defined by in vivo Evans blue dye injection and subsequent light microscopy. Scanning and transmission electron microscopy will be used to provide detailed information regarding endothelial abnormalities for correlation with functional data. The above studies will be followed in the second and third years by investigation of the effect of acute endothelial disruption at various stages of atherosclerosis. In addition, parallel studies on fresh postmortem human coronary arteries with varying degrees of atherosclerosis will also be performed, guided by the porcine studies.